Molecular
Structure and Molecular Engineering
We are
studying the molecular mechanisms that confer specific
shapes on proteins, and which determine how proteins
recognize small molecules. The goal is to elucidate
predictive principles by which novel structures and
catalytic properties can be conferred accurately on
designed polypeptides, and to achieve the rational design
of ligands for proteins of known conformation. The lab
relies primarily on three tools: (a) the computational
engineering of structures at atomic resolution, made
possible by the advent of classical molecular mechanics
potentials (b) biophysical characterization of peptide
proteins composed from an expanded amino acid alphabet
(c) the generation and screening of combinatorial
libraries, both in vivo using bacterial screens and
sexual PCR and in vitro by synthesis of compounds on
solid support.
The lab is divided into two main areas of research. The
first group is focused on the computational design and
experimental verification of novel a/b barrel proteins.
The a/b barrel fold was chosen because of the structural
regularity of its naturallyoccurring examples, because
its tetrameric point symmetry reduces the asymmetric unit
that must be designed, because it supports a wide variety
of catalytic functions that are amenable to selection,
and because its constituent secondary structures can be
subjected to backbone parameterization. Computational
engineering of fourfold symmetric a/b barrels requires
the exploration of eight backbone degrees of freedom and
of sidechain identity at ten core positions, which lies
within the reach of current algorithms and hardware. The
designed barrel sequences are made by peptide synthesis
and are characterized structurally. Designed a/b barrels
will be outcrossed against naturally occurring catalytic
a/b barrels to determine a minimal set of mutations
required to confer catalytic activity on the designed
scaffolds.
The second group is focused on the synthesis, screening
and crystallographicallyguided optimization of
small-molecule libraries based on athio bamino acid
polymers. These polymers are particularly suitable
pharmaceutical substrates because of the diversity they
afford per unit molecular weight, because their chemical
structure is expected to confer favorable pharmacokinetic
properties, and because their synthesis is both modular
and expedient. Methods are being developed to express
athio bamino acid polymers biosynthetically using a
modified in vitro translation extract, and to select for
binding to macromolecular targets using polyribosome
display. Cocrystal structures of lead compounds will be
used to computationally screen the enormous number of
possible generating monomers present in the Fine Chemical
Directory, and to thereby develop predictions for ligand
improvement that may be rapidly tested.
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